rs186784974

Variant names:

• chr18-45901140-C-T
• rs186784974
• NM_020964.3:c.4502G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020964.3(EPG5):​c.4502G>A​(p.Arg1501Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,614,068 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1501W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (2 hom.)
• Consequence: EPG5 NM_020964.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.451
• Publications: 5 publications found

Genes affected

EPG5 (HGNC:29331): (ectopic P-granules 5 autophagy tethering factor) This gene encodes a large coiled coil domain-containing protein that functions in autophagy during starvation conditions. Mutations in this gene cause Vici syndrome. [provided by RefSeq, Aug 2015]

EPG5 Gene-Disease associations (from GenCC):

• Vici syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003628403).
• BP6: Variant 18-45901140-C-T is Benign according to our data. Variant chr18-45901140-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 466250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020964.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	NM_020964.3	MANE Select	c.4502G>A	p.Arg1501Gln	missense	Exon 26 of 44	NP_066015.2	Q9HCE0-1
	EPG5	NM_001410859.1		c.4502G>A	p.Arg1501Gln	missense	Exon 26 of 44	NP_001397788.1	A0A8Q3SIU6
	EPG5	NM_001410858.1		c.4502G>A	p.Arg1501Gln	missense	Exon 26 of 44	NP_001397787.1	A0A8Q3SIJ2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPG5	ENST00000282041.11	TSL:1 MANE Select	c.4502G>A	p.Arg1501Gln	missense	Exon 26 of 44	ENSP00000282041.4	Q9HCE0-1
	EPG5	ENST00000587884.2	TSL:1	n.*242G>A		non_coding_transcript_exon	Exon 27 of 45	ENSP00000466990.2	K7ENK5
	EPG5	ENST00000590884.6	TSL:1	n.4502G>A		non_coding_transcript_exon	Exon 26 of 42	ENSP00000466403.2	K7EM87

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000795 AC: 198 AN: 248928 AF XY: 0.000851

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.000677 AC: 989 AN: 1461794 Hom.: 2 Cov.: 31 AF XY: 0.000700 AC XY: 509 AN XY: 727200

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00136 AC: 61 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53360

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000697 AC: 775 AN: 1111992

Other (OTH) AF: 0.00106 AC: 64 AN: 60394

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.000806 AC XY: 60 AN XY: 74460

African (AFR) AF: 0.000265 AC: 11 AN: 41550

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000926 AC: 63 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00100 Hom.: 3

Bravo AF: 0.000990

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000967 AC: 8

ExAC AF: 0.000703 AC: 85

EpiCase AF: 0.00125

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	EPG5-related disorder (1)
-	-	1	Vici syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.79	N
PhyloP100		0.45
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.11
Sift	Benign	0.40	T
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.090
MVP		0.076
MPC		0.17
ClinPred		0.013	T
GERP RS		-5.8
Varity_R		0.021
gMVP		0.071
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs186784974; hg19: chr18-43481105; COSMIC: COSV99957063;